Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-22 have an effective filing date of 23 APR 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/05/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 1-22 are currently pending and presented for examination on the merits.
Claim Objections
Claim 1 is objected to for not reciting a complete pre-amble.
Claim 18 is objected to for depending from a rejected claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
5. Claims 1-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. In the instant case the claims are drawn to a natural phenomenon, specifically, the relationship between NID1 levels and a diagnosis of hepatocellular carcinoma (HCC). Furthermore the claims do not integrate said judicial exception in to practical application, and the claims do not recite additional elements that amount to significantly more than said judicial exception.
6. The 2019 Patent Subject Matter Eligibility Guidance (“Guidance”) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
7. Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
8. Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
9. Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
10. With respect to Step 1, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
11. With respect to prong one of Step 2A, the answer is “Yes,” because the claims are drawn to a natural phenomenon, specifically, the relationship between NID1 levels and a diagnosis of HCC.
12. With respect to prong two of Step 2A, the claims do not recite additional elements that integrate the judicial exception into a practical application. In addition to the recited judicial exception, the claims recite obtaining a sample from the subject, centrifuging the sample to obtain serum, isolating and lysing extracellular vesicles, contacting the sample with a biomarker composition, measuring and comparing a level of the NID1 with a control, and diagnosing the subject having HCC if the level of the NID1 is higher than the control; however these steps primarily relate to routine laboratory practices involving detecting protein expression. As such these steps do not integrate the judicial exception into a practical application. The claims also do not recite any additional method steps that would integrate the recited judicial exception, for example, by applying or using said judicial exception as an indicator to determine whether a particular treatment or prophylaxis for a disease or medical condition should be administered. It is further noted that the claims include an “comparing” and “diagnosing” step, see claim 1, and these steps are abstract ideas, which involves steps that may be carried out by the human mind. Therefore the answer to prong two of the Step 2A analysis is “No.”.
13. With respect to Step 2B, as indicated above, the claims recite steps related to routine laboratory practices involving detecting protein expression; however these steps were well-understood, routine, and conventional data gathering steps that were practiced by investigators prior to Applicant’s invention. These steps, alone or in combination, fail to qualify as to additional elements that amount to significantly more than the recited judicial exception. Accordingly the answer to the Step 2B analysis is “No,” and therefore the claims are not eligible subject matter under 35 U.S.C. 101.
Claim 2 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. In the instant case the claim is drawn to a natural phenomenon, specifically, the relationship between TNFR1 and AFP levels and a diagnosis of hepatocellular carcinoma (HCC). Furthermore the claim does not integrate said judicial exception in to practical application, and the claims do not recite additional elements that amount to significantly more than said judicial exception.
The 2019 Patent Subject Matter Eligibility Guidance (“Guidance”) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
With respect to Step 1, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because the claim is drawn to a natural phenomenon, specifically, the relationship between TNFR1 and AFP levels and a diagnosis of HCC.
With respect to prong two of Step 2A, the claims do not recite additional elements that integrate the judicial exception into a practical application. In addition to the recited judicial exception, the claims recite obtaining a sample from the subject, centrifuging the sample to obtain serum, isolating and lysing extracellular vesicles, contacting the sample with a biomarker composition, measuring and comparing a level of the TNFR1 and AFP with a control, and diagnosing the subject having HCC if the level of the TNFR1 and AFP is higher than the control; however these steps primarily relate to routine laboratory practices involving detecting protein expression. As such these steps do not integrate the judicial exception into a practical application. The claims also do not recite any additional method steps that would integrate the recited judicial exception, for example, by applying or using said judicial exception as an indicator to determine whether a particular treatment or prophylaxis for a disease or medical condition should be administered. It is further noted that the claims include an “comparing” and “diagnosing” step, see claim 1, and this step is an abstract idea, which involves steps that may be carried out by the human mind. Therefore the answer to prong two of the Step 2A analysis is “No.”.
With respect to Step 2B, as indicated above, the claims recite steps related to routine laboratory practices involving detecting protein expression; however these steps were well-understood, routine, and conventional data gathering steps that were practiced by investigators prior to Applicant’s invention. These steps, alone or in combination, fail to qualify as to additional elements that amount to significantly more than the recited judicial exception. Accordingly the answer to the Step 2B analysis is “No,” and therefore the claim is not eligible subject matter under 35 U.S.C. 101.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 and 19-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 9, and 17 are drawn to an antibody that binds NID1, wherein said antibody comprises a VH having at least 80% sequence identity with SEQ ID NO: 41 and a VL having at least 80% sequence identity with SEQ ID NO: 42. The claims encompass a large number of anti-NID1 antibodies having diverse heavy and light chain CDR amino acid sequences. Following a review of the specification, it appears that Applicant has disclosed one anti-NID1 antibody, specifically, an anti-NID1 antibody that comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 42; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple anti-NID1 antibodies having diverse heavy and light chain CDR sequences. Even though Applicant has disclosed one species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to antibody molecules capable of binding NID1. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences, 1982, 79:1979-1983). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
MacCallum et al. (Journal of Molecular Biology, 1996, 262:732-745) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominates, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset et al. (Biochemical and Biophysical Research Communications, 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except CDR L2 and additionally using a framework residue located just before the CDR H3 (see page 202, left column). Holm et al. (Molecular Immunology, 2007:1075-1084) describes the mapping of an anti-cytokeratin antibody and found that in addition to the involvement of the residues in the CDR3 of the heavy chain in antigen binding, a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (Journal of Molecular Biology, 1999, 293:865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). There is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of an antibody to bind to NID1 comprising fewer than 6 complete CDR regions of an antibody known to bind NID1.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In the instant case, Applicant has disclosed one species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of one species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind NID1. Absent a description of the at least minimal structural features correlating with a functional ability to bind NID1 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to bind NID1.
Although screening techniques can be used to isolate antibodies that possess the ability to bind NID1, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Claim 19 is included in this rejection, because the claim allows for anti-NID1 antibodies having variability within the heavy and light chain CDRs. Absent empirical determination one skilled in the art would be unable to readily determine which variants of the recited CDRs should be comprised within an antigen-binding site, such that said antigen-binding site is capable of binding NID1.
Claim 20 is included in this rejection, because the claim is drawn to the administration of any anti-NID1 monoclonal antibody; however screening methodologies would be required to determine whether a particular anti-NID1 monoclonal antibody is capable of both binding to NID1 and treating cancer. For example it is noted that the claim encompasses both agonistic and antagonistic anti-NID1 monoclonal antibodies. Furthermore one skilled in the art would reason that an anti-NID1 monoclonal antibody would likely only treat NID1-expressing cancers, but the claim is drawn to the treatment of any cancer type. Applicant is thus advised to amend the claim to recite a method of treating a NID1-expresing cancer, as the breadth of cancers claimed lack adequate support.
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Aleckovic et al (Identification of Nidogen 1 as a lung metastasis protein through secretome analysis, Genes & Dev, 31, pgs. 1439-1455, IDS 05/05/2025), and further in view of Moretta et al (WO2019206974 A1, IDS 05/05/2025).
With regards to claim 20, Aleckovic et al teaches NID1 is a promoter of lung metastasis in different types of cancers [Left column, 2nd Paragraph, pg. 1440]. Aleckovic et al further teaches NID1 expression correlates with a poor prognosis and lung relapse [Left column, 2nd Paragraph, pg. 1440]. Aleckovic et al further teaches NID1 is a biomarker for high risk lung metastasis and a therapeutic target for preventing cancer lung metastasis [Left column, 2nd Paragraph, pg. 1440]. Aleckovic et al further teaches administering an anti-NID1 antibody to NID1 overexpressing cancer cells and observing a significant reduction in tube formation to levels of control cells [Left column, 3rd Paragraph, pg. 1447].
Aleckovic et al does not specifically teach an anti-cancer agent. However, this deficiency is made up in the teachings of Moretta et al.
Moretta et al teaches “[i]n some embodiments, the technology described herein relates to antibodies and antibody fragments (e.g. comprising an antigen-binding portion of an antibody which binds a NID1 polypeptide).” [Lines 27-31, pg. 2]. Moretta et al further teaches a method of treating cancer by targeting NID1. Moretta et al further teaches additionally administering an anti-cancer agent [Lines 17-28, pg. 26].
One of ordinary skill in the art, before the effective filing date, would have been motivated to use Aleckovic’s method of inhibiting NID1 to decrease cancer metastasis to the lung, with Moretta’s method of treating cancer by administering an anti-NID1 antibody and an anti-cancer agent. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine Aleckovic and Moretta’s methods for a method of treating cancer in a subject comprising administering an anti-NID1 monoclonal antibody and an anti-cancer agent, because there would have been a reasonable expectation that such a method would provide a therapeutic benefit to lung cancer patients.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 12099061 ('061). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With regards to claim 20, instant claim 20 is not patentable distinct from claims 1-2 of ‘061. Specifically, a method of treating cancer comprising administering an anti-NID1 antibody (claim 1).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642